Definition
Ovarian cancer is a malignant neoplasm originating from the uncontrolled proliferation of the cells composing the organ, in most cases from epithelial cells. Germ cells and stromal cells, which represent the other main ovarian cellular components, may also be the origin of a neoplasm. Ovarian cancer most frequently affects women aged 50 to 69 years.
Risk and protective factors
Among factors that may influence ovarian cancer risk, age represents one of the principal elements. Additional conditions associated with increased risk include obesity, early menarche, late menopause, and nulliparity. Conversely, a higher number of pregnancies, breastfeeding, and prolonged use of combined estrogen-progestogen contraceptives are associated with a reduced risk of developing this neoplasm.
It is also well documented that the presence of germline and/or somatic genetic mutations may predispose to the onset of various neoplasms. These include mutations of the BRCA1 and BRCA2 genes. The presence of a BRCA1 mutation entails an increase in ovarian cancer risk of approximately 15–45% compared to the general population, while BRCA2 mutation is associated with a risk increase between 10 and 20%. These genetic alterations also carry a higher risk of other neoplasms, particularly of the breast. For this reason, in selected patients, a prophylactic intervention may be indicated, providing for bilateral oophorectomy, with or without combined bilateral mastectomy.
Symptoms
In the early stages, ovarian cancer is often without specific symptoms. For this reason, it has traditionally been called the "silent killer", as diagnosis frequently occurs at an advanced stage when the disease has already reached significant spread. Symptoms that may appear are generally non-specific but deserve attention as possible warning signs.
Among the most frequent are abdominal bloating, marked meteorism, and increased urinary frequency. Other possible symptoms include abdominal or pelvic pain, vaginal bleeding, constipation, and/or diarrhea. Nausea, reduced appetite, and a sense of early satiety appear more often in the more advanced stages of the disease.
Caution: the combination of persistent abdominal bloating, increase in abdominal circumference, and urinary urgency — especially if of recent onset and frequent — requires prompt specialist evaluation with pelvic ultrasound and CA-125 testing.
Diagnosis
Diagnosis is frequently made late, when the neoplasm has already extended into the abdomen. After physical examination, the first-level investigation is represented by transabdominal ultrasound or, preferably, transvaginal ultrasound, combined with CA-125 testing, a serum marker that may be elevated in the presence of this disease.
Once the diagnostic indication of ovarian neoplasm is established, abdominal CT and magnetic resonance imaging are used to define disease extent and assess for any metastases in the abdominal cavity or distant sites.
Treatment
Surgery combined with chemotherapy currently represents the cornerstone of ovarian cancer treatment; however, it is essential to personalize treatment based on the biological and clinical characteristics of the disease. Surgical intervention varies according to stage and is potentially curative in approximately 70% of tumors diagnosed in the initial stage. The goal of surgery is to achieve residual disease equal to 0 (RT=0), that is, the absence of macroscopically visible disease.
In advanced stages, the surgical approach may involve two strategies: primary surgery or interval surgery after administration of multiple cycles of platinum-based chemotherapy, with the goal of reducing tumor mass. However, not all patients are candidates for upfront surgical treatment.
Clinical framework
Cytoreduction in ovarian carcinoma represents one of the cornerstones of treatment for advanced epithelial ovarian cancer and continues to be a central topic in gynecologic oncology. Ovarian carcinoma, due to its biological characteristics, intraperitoneal distribution, and clinical presentation patterns, requires complex specialist evaluation, in which therapeutic planning must integrate surgical, oncologic, and overall patient-condition data.
Rationale of cytoreductive surgery
For a long time, the traditional approach to surgery in ovarian carcinoma was based on the principle of maximum possible cytoreduction. In this model, the primary goal of intervention is the removal of macroscopically visible disease, since the extent of postoperative tumor residual represents one of the principal prognostic determinants. Historical evidence has shown that increased rates of complete or optimal cytoreductive surgery are associated with improved survival, confirming the oncologic value of surgical radicality when appropriate.
Limits of extensive surgery and predictive factors of suboptimal cytoreduction
Clinical experience has nonetheless clarified that not all patients with advanced ovarian carcinoma are candidates for an extensive surgical approach with reasonable probability of benefit. The presence of predictive factors of suboptimal cytoreduction, such as diffuse hepatic metastases, massive involvement of the hepatic hilum, or infiltration of the superior mesenteric artery, identifies situations in which surgery may be particularly aggressive, with high technical complexity and increased perioperative risk. Studies dedicated to upper abdomen procedures have documented in this context non-negligible morbidity, highlighting how demolitive surgery should be reserved for cases in which the goal of adequate cytoreduction is concretely achievable.
From maximum possible intervention to maximum tolerable treatment
The evolution of knowledge has determined a progressive paradigm shift in the management of advanced ovarian carcinoma. Today the decisional criterion can no longer coincide exclusively with the maximum extent of feasible surgery, but must orient toward the maximum tolerable treatment. The surgical result is evaluated not only in terms of absence of macroscopic residual, but also in light of the impact on quality of life, postoperative morbidity, and the possibility of correctly completing subsequent systemic treatment.
Guidelines and therapeutic selection
This orientation is consistent with what is reported by the main international guidelines, including NCCN and ESGO, which have progressively refined criteria related to cytoreductive surgery and, in specific contexts, lymphadenectomy. Contemporary recommendations emphasize the need for accurate selection, based on disease extent, resectability, performance status, and the balance between expected oncologic benefit and surgical risk. Treatment of ovarian carcinoma therefore requires a structured multidisciplinary decision, in which the operative indication must be inserted into a comprehensive therapeutic pathway.
Frailty, biological age, and treatment personalization
An increasingly relevant element in the decisional process is represented by preoperative frailty assessment. Available evidence shows that frailty constitutes an independent predictor of adverse outcomes, influencing the risk of complications, length of stay, probability of readmission, and the possibility of accessing adjuvant chemotherapy in appropriate timing. Simple chronological age is not sufficient to guide therapeutic choices: it is necessary to consider biological age, functional reserve, comorbidities, and the patient's overall capacity to tolerate major surgical treatment.
Integration with targeted therapies
The introduction of targeted therapies has further modified the therapeutic landscape of ovarian carcinoma. PARP inhibitors have redefined treatment prospects in selected patients, significantly influencing progression-free survival. A sub-analysis of the SOLO1 trial documented that the integration of PARP inhibitors into the therapeutic pathway — both after primary debulking surgery and after interval debulking surgery — must be considered in overall strategy planning. It follows that the choice between PDS and IDS cannot be evaluated only in technical terms, but must be inserted into a broader vision encompassing tumor biology, molecular profile, and available maintenance options.
Conclusions
Contemporary management of ovarian carcinoma requires a highly selective and personalized approach. Cytoreduction remains a fundamental element of treatment, but its indication must be defined on the basis of a decisional model that integrates disease extent, probability of complete resection, patient frailty, and availability of effective systemic therapies. In this context, the experience of the gynecologic oncology surgeon and multidisciplinary evaluation assume a determining role in building a coherent, proportionate, and clinically appropriate therapeutic pathway.
The risk of recurrence remains high, approximately 25–30%, and for this reason adjuvant chemotherapy is sometimes employed after surgery, generally based on carboplatin and paclitaxel. In the treatment of ovarian cancer, targeted molecular agents are also available. These include the monoclonal antibody bevacizumab, which acts by interfering with tumor angiogenesis, and PARP inhibitors, including olaparib, niraparib, and rucaparib.
Maintenance therapy with PARP inhibitors has proven particularly effective in tumors associated with BRCA1 or BRCA2 mutations, while retaining activity even in cases without mutation.
Prevention
Currently, no scientifically reliable screening programs are available for the early diagnosis of ovarian cancer. For this reason, periodic gynecologic examination combined with control transvaginal ultrasound may contribute to timely assessment of any suspicious abnormalities. In women with established genetic predisposition (BRCA1/2 variants or Lynch syndrome), oncogenetic counseling and the planning of a personalized surveillance or risk-reduction strategy are indicated.
Ovarian cancer has long been called the "silent killer", but available data indicate that most patients report symptoms before diagnosis, predominantly abdominal and gastrointestinal. The most frequent symptoms include persistent abdominal bloating, increase in abdominal circumference, abdominal or pelvic pain, difficulty eating or sense of early satiety, as well as urinary urgency and increased frequency.
The association between bloating, increased abdominal circumference, and urinary urgency was observed in 43% of ovarian cancer patients compared to 8% of women without cancer (OR 9.4). An analysis of insurance databases highlighted that 54% of patients receive a diagnosis of gastrointestinal disorder — particularly gastroesophageal reflux disease — in the year preceding the cancer diagnosis. Symptoms such as dyspepsia, bowel changes, and constipation are often initially attributed to irritable bowel syndrome or other benign conditions, with possible diagnostic delay.
Ref.: [1, 2, 4, 5, 6]
Routine gynecologic examination has limited capacity to identify ovarian cancer early. Pelvic examination may sometimes detect a palpable mass or the presence of ascites, but in most early-stage ovarian cancers no specific objective findings are detected.
The U.S. Preventive Services Task Force (USPSTF) in 2018 recommended against screening for ovarian cancer in asymptomatic women at average risk, as neither transvaginal ultrasound nor CA-125 has been shown to reduce mortality. Gynecologic examination nonetheless maintains a fundamental role in history taking, evaluation of symptoms and family history, and in guiding any diagnostic workup in the presence of clinical suspicion.
Ref.: [1, 7]
CA-125 has limited reliability as an early-diagnosis tool. It is elevated in approximately 80% of advanced-stage epithelial ovarian carcinomas, while sensitivity for stage I disease is only 25–50%. In postmenopausal women, sensitivity ranges from 69 to 87% and specificity from 81 to 93%, while in premenopausal women specificity is significantly reduced due to the presence of numerous benign conditions that may cause an increase in the marker, including endometriosis, pregnancy, inflammatory bowel disease, and renal failure.
The PLCO study and the UKCTOCS trial (N = 271,103) did not demonstrate a significant reduction in mortality with annual screening programs based on CA-125 and/or transvaginal ultrasound. The HE4 marker has higher specificity than CA-125, especially in premenopausal women, and can be integrated into the calculation of the ROMA (Risk of Ovarian Malignancy Algorithm).
Ref.: [1, 3, 8, 9]
Yes. The use of combined oral contraceptives is associated with a significant reduction in ovarian cancer risk. A meta-analysis of 45 epidemiologic studies, including 23,257 cases and 87,303 controls, documented a 20% risk reduction for every 5 years of use. Use exceeding 10 years is associated with an OR of 0.43 (95% CI: 0.37–0.51).
This protective effect is also observed in BRCA1/2 variant carriers, with approximately 50% risk reduction (SRR 0.50; 95% CI: 0.33–0.75). NCCN guidelines indicate that oral contraceptives may be considered a risk-reduction strategy in high-risk women who do not undergo prophylactic salpingo-oophorectomy.
Ref.: [1, 10, 11, 12]
The ultrasound characteristics that allow distinction between a benign and a suspicious lesion are well defined. The IOTA (International Ovarian Tumor Analysis) rules identify:
- Benign characteristics (B-features): unilocular cyst, absence of solid components (or small solid component <7 mm), acoustic shadows, smooth multilocular surface with diameter <10 cm, absence of blood flow.
- Malignant characteristics (M-features): irregular solid mass, ascites, at least four papillary structures, irregular multilocular-solid mass >10 cm, very intense Doppler flow.
Simple, unilocular cysts with thin and regular walls, without solid components or septa, are almost always benign, with a malignancy rate between 0 and 1%, regardless of menopausal status. ACOG recommends that simple cysts up to 10 cm may be followed with serial ultrasound monitoring without immediate surgical indication.
Ref.: [8, 13]
The cumulative risk of ovarian cancer by age 80 is 44% (95% CI: 36–53%) in BRCA1 carriers and 17% (95% CI: 11–25%) in BRCA2 carriers. NCCN guidelines report an absolute risk of 39–58% for BRCA1 and 13–29% for BRCA2. The incidence is higher in BRCA1 than BRCA2 carriers (HR 3.6) and increases with age, with a peak between 61 and 70 years.
Prophylactic bilateral salpingo-oophorectomy reduces the risk of ovarian cancer by 81% (HR 0.19; 95% CI: 0.13–0.27) and is recommended at age 35–40 for BRCA1 carriers and 40–45 for BRCA2 carriers.
Ref.: [1, 12, 14]
Persistent abdominal bloating is not always an expression of ovarian cancer, but it represents the most frequently reported symptom by patients, present in 70% of cases compared to 38% of controls. NICE guidelines recommend diagnostic workup with CA-125 and pelvic ultrasound when bloating is persistent, of recent onset, and present more than 12 times per month, especially if associated with other symptoms such as abdominal or pelvic pain, early satiety, or urinary urgency, particularly in women over 50 years of age.
What distinguishes "sentinel" bloating from functional bloating is mainly its recent onset, frequency, and greater intensity.
Ref.: [1, 2, 3]
Beyond family history and age — whose median at diagnosis is 63 years — the main ovarian cancer risk factors include:
- Endometriosis: HR 4.20 (95% CI: 3.59–4.91)
- Infertility: SIR 2.0 (95% CI: 1.8–4.0)
- Postmenopausal estrogen therapy: RR 1.31 (95% CI: 1.21–1.41)
- Nulliparity and absence of breastfeeding
- Genetic mutations: BRCA1/2, mismatch repair genes (MLH1, MSH2, MSH6)
Protective factors include multiparity (OR 0.81 for each additional birth), breastfeeding (OR 0.72), and oral contraceptive use (OR 0.66).
Ref.: [1, 15]
Risk-reducing bilateral salpingo-oophorectomy (RRSO) consists of complete surgical removal of both ovaries and fallopian tubes. The intervention includes:
- Recommended timing: 35–40 years for BRCA1, 40–45 years for BRCA2, 45–50 years for other pathogenic variants such as Lynch syndrome.
- Preoperative evaluation: CA-125 and pelvic ultrasound for surgical planning purposes.
- Pathology protocol: SEE-FIM (Sectioning and Extensively Examining the Fimbriated End) for accurate histologic examination of the fimbriae, combined with peritoneal washing.
- Efficacy: reduction of ovarian cancer risk by approximately 80% (HR 0.19–0.21), with a small residual risk of primary peritoneal carcinoma.
- Side effects: early surgical menopause with possible appearance of vasomotor symptoms, osteoporosis, cardiovascular pathology, and sexual dysfunction. Hormone replacement therapy is generally not contraindicated in premenopausal women without a personal history of breast carcinoma.
Ref.: [1, 12, 16]
Advanced-stage ovarian cancer (III–IV) presents a 5-year survival between 10 and 40% with standard treatment based on cytoreductive surgery and platinum-based chemotherapy. The initial complete remission rate is approximately 80%, but about 75% of patients experience recurrence within 2 years. Patients with BRCA variants or HRD-positive status treated with PARP inhibitors may achieve a 5-year survival of approximately 70%.
Approximately 18% of stage III patients can be considered potentially cured, with disease-free survival ≥10 years. Optimal cytoreductive surgery, with absence of macroscopically visible residual disease (RT=0), represents the principal independent prognostic factor.
Ref.: [1, 17, 18]
Specialist Consultation Request
For ovarian cancer risk assessment, a surgical second opinion, or planning of a risk-reduction pathway in women with BRCA mutation, you may request a consultation with Prof. Di Donato.
Book a consultation →